Protein monoubiquitylation: targets and diverse functions

Abstract

Ubiquitin is a 76‐amino acid protein whose conjugation to protein targets is a form of post‐translational modification. Protein ubiquitylation is characterized by the covalent attachment of the COOH‐terminal carboxyl group of ubiquitin to an amino group of the substrate protein. Given that the NH2‐terminal amino group is usually masked, internal lysine residues are most often targeted for ubiquitylation. Polyubiquitylation refers to the formation of a polyubiquitin chain on the substrate as a result of the ubiquitylation of conjugated ubiquitin. The structures of such polyubiquitin chains depend on the specific lysine residues of ubiquitin targeted for ubiquitylation. Most of the polyubiquitin chains other than those linked via lysine‐63 and methionine‐1 of ubiquitin are recognized by the proteasome and serve as a trigger for substrate degradation. In contrast, polyubiquitin chains linked via lysine‐63 and methionine‐1 serve as a binding platform for proteins that function in immune signal transduction or DNA repair. With the exception of a few targets such as histones, the functions of protein monoubiquitylation have remained less clear. However, recent proteomics analysis has shown that monoubiquitylation occurs more frequently than polyubiquitylation, and studies are beginning to provide insight into its biologically important functions. Here, we summarize recent findings on protein monoubiquitylation to provide an overview of the targets and molecular functions of this modification.

Delineating Crosstalk Mechanisms of the Ubiquitin Proteasome System That Regulate Apoptosis

“…Here, protein substrates are first tagged through the covalent attachment of single or multiple ubiquitin moieties, and the tagged proteins ultimately get degraded by the 26S proteasome and their component amino acids eventually recycled (Figure 1 ). Over the years, the general notion of proteasomal degradation has been that of recognition of polyubiquitination chain of four or more ubiquitin attached to substrate protein by the proteasome (Thrower et al, 2000 ) but increasing number of studies suggests that even monoubiquitination or multi-monoubiquitination (Figure 2 ) is adequate to degrade small substrates that are longer than 20 amino acids but smaller than 150 residues (Shabek et al, 2007 , 2009 , 2012 ; Nakagawa and Nakayama, 2015 ). Protein ubiquitination and degradation is a three-cascade mechanism as explained in Figure 1 .…”

Expanding Role of Ubiquitin in Translational Control

“…The number of specific functions of ubiquitin are exponentially increased when the combination of polyubiquitin linkages is considered in addition to the functions of monoubiquitin. Monoubiquitin is known to play a role in transcriptional control, DNA repair, metabolism, and apoptosis [60]. Homotypic chains, the more well-studied types of the polyubiquitin chains, are designated by the lysine position that defines the linkage.…”

Ubiquitylation-Mediated Fine-Tuning of DNA Double-Strand Break Repair

“…Although less information is known about monoubiquitylation, it has diverse effects on cellular processes. For instance, it plays a role in contributing to nuclear export-import, the chromatin recruitment or dissociation of certain proteins and also participates in protein degradation [3]. During polyubiquitylation, certain internal lysine residues (K6, K11, K27, K29, K33, K48 and K63) of ubiquitin serve as acceptor sites for the binding of additional ones [1].…”